The goal of this project is to examine the manner in which immunologic mechanisms may contribute to diseases of the nervous system. The cellular and humoral immune response to putative antigens and possible immunopathologic disease such as multiple sclerosis (MS) are being studied. Included in these studies have been examinations of the immune response to viruses which can commonly infect the nervous system and which could be related to the induction of immunopathologic disease processes. In addition, the immune response to antigens of myelin such as myelin basic protein (MBP) and proteolipid protein (PLP) which may represent targets of immune-mediated diseases of myelin, has been studied. T-cell response to these antigens is being examined in patients with clinically definite MS and healthy controls, in members of MS multiplex families, and in identical and nonidentical twins, either concordant or discordant for MS. Various parameters of the T-cell response to myelin antigens is being examined, including frequency, peptide specificity, and HLA restriction. The T-cell response to myelin antigens other than the 18.5kDa form of MBP have been examined. These include the protein encoded by the exon 2, which is expressed in the 21.kDa form of MBP found in developing myelin, the C8 form of MBP that has 6 citrulline substitutions for alanine in the 18.5kDa form, and PLP. A substantial T-cell response to exon 2 and to C8 has been demonstrated indicating that, although these proteins are found in extremely low concentrations of the nervous system, they appear to be immunogenic and could potentially represent target autoantigens in autoimmune diseases of the nervous system. Studies of PLP have employed synthetic peptides and have demonstrated a response that appears to be immunodominant to portions of the PLP molecule. No substantial differences in these responses between patients and healthy controls have been noted. In addition, the T-cell response to viruses which have been implicated previously in MS such as measles virus are being examined. The parameters of the normal T-cell response following natural infection or vaccination are being studied. The humoral and cellular immune response to measles virus is being examined in individuals previously vaccinated, but lacking evidence of immunity.